RESUMEN
To investigate the metabolism of nascent HDLs, apoA1/phosphatidylcholine (apoA1/PC) discs were infused IV over 4 hours into 7 healthy men. Plasma total apoA1 and phospholipid (PL) concentrations increased during the infusions. The rise in plasma apoA1 was greatest in small prebeta-migrating particles not present in the infusate. Total HDL unesterified cholesterol (UC) also increased simultaneously. After stopping the infusion, the concentrations of apoA1, PL, HDL UC, and small prebeta HDLs decreased, whereas those of HDL cholesteryl ester (CE) and large alpha-migrating apoA1 containing HDLs increased. ApoB-containing lipoproteins became enriched in CEs. Addition of apoA1/PC discs to whole blood at 37 degrees C in vitro also generated small prebeta HDLs, but did not augment the transfer of UC from erythrocytes to plasma. We conclude that the disc infusions increased the intravascular production of small prebeta HDLs in vivo, and that this was associated with an increase in the efflux and esterification of UC derived from fixed tissues. The extent to which the increase in tissue cholesterol efflux was dependent on that in prebeta HDL production could not be determined. Infusion of discs also reduced the plasma apoB and apoA2 concentrations, and increased plasma triglycerides and apoC3. Thus, nascent HDL secretion may have a significant impact on prebeta HDL production, reverse cholesterol transport and lipoprotein metabolism in humans.
Asunto(s)
Apolipoproteína A-I/administración & dosificación , Lipoproteínas/sangre , Fosfatidilcolinas/administración & dosificación , Adulto , Apolipoproteína A-I/efectos adversos , Apolipoproteína A-I/sangre , Apolipoproteína A-II/sangre , Apolipoproteínas B/sangre , Apolipoproteínas C/sangre , Colatos/sangre , Cromatografía en Gel , Combinación de Medicamentos , Humanos , Inmunoelectroforesis Bidimensional , Infusiones Intravenosas , Masculino , Fosfatidilcolinas/efectos adversos , Fosfolípidos/sangreRESUMEN
A reconstituted high density lipoprotein (rHDL) prepared for clinical use was tested for its influence on platelet activity modulated by various stimuli. In a first series of in vitro experiments, rHDL was added to blood in a concentration series, and platelet rich plasma (PRP) was isolated. Platelets were stimulated with arachidonic acid, collagen, epinephrine or ADP, and platelet aggregation was assessed. rHDL mediated a dose dependent inhibition of the platelet activity. With purified platelets rHDL inhibited the release reaction induced by collagen, but not by thrombin, as measured by CD62P (P-Selectin) expression on the plasma membrane. Ex vivo experiments were performed with PRP from volunteers, previously infused with 25 mg rHDL/kg body weight and 40 mg rHDL/kg body weight, respectively. Platelet activity in PRP was assessed before, and up to 30 h after the end of the rHDL infusion. A transient inhibition of the platelet aggregation induced by arachidonic acid and collagen was observed which was more pronounced in the group receiving 40 mg rHDL/kg body weight. In both groups of experiments, in vitro and ex vivo, the inhibition of the platelet activity was also dependent on the stimulus used.
Asunto(s)
Lipoproteínas HDL/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Humanos , Infusiones Intravenosas , Lípidos/sangre , Masculino , Valores de ReferenciaRESUMEN
A reconstituted high density lipoprotein (rHDL) containing human apolipoprotein A-I and phosphatidylcholine was tested for its ability to modify polymorphonuclear leukocyte (PMN) adherence to endothelial cells (EC) in vitro. EC stimulation for 4 h with lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF alpha) resulted in a four- to sixfold increase in PMN adherence. Concomitant stimulation of EC with LPS and rHDL virtually prevented the LPS-stimulated increase in PMN adherence. Changes in adherence were paralleled by alterations in adhesion molecule expression of EC. Concomitant EC stimulation with LPS and rHDL resulted in complete inhibition of the LPS-stimulated increase in expression of E-selectin and intercellular adhesion molecule 1 (ICAM-1). In contrast, rHDL reduced the TNF alpha-induced expression of adhesion molecules as well as the PMN adherence to TNF alpha-stimulated EC by approximately 10%. The CD11/CD18-mediated PMN adherence to EC as a consequence of PMN stimulation with calcium ionophore (A23187) was diminished in the presence of rHDL after 7 min incubation by 36.1 +/- 11.4% and after 15 min incubation by 45.1 +/- 7.4%. In addition, the A23187-stimulated increase in PMN adherence to fibrinogen-coated surfaces, mediated by CD11b/CD18, was virtually eliminated in the presence of rHDL and HDL, but not in the presence of apolipoprotein A-I or natural low density lipoprotein. FACS analysis showed that PMN treated with rHDL and subsequently washed were resistant to FMLP-induced CD11b/ CD18 up-regulation. In conclusion, these data indicate that rHDL decreases cell adhesion via two mechanisms: blocking LPS activity and modifying CD11b/CD18 up-regulation on PMN.
Asunto(s)
Endotelio Vascular/citología , Lipoproteínas HDL/fisiología , Neutrófilos/citología , Apolipoproteína A-I/farmacología , Antígenos CD11/metabolismo , Antígenos CD18/metabolismo , Calcimicina/farmacología , Adhesión Celular/fisiología , Células Cultivadas , Selectina E/metabolismo , Fibrinógeno/farmacología , Humanos , Integrinas/metabolismo , Molécula 1 de Adhesión Intercelular/biosíntesis , Lipopolisacáridos/farmacología , Antígeno de Macrófago-1/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/inmunología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
High-density lipoproteins (HDL) can bind and neutralize lipopolysaccharides (LPS) in vitro and in vivo. HDL can also affect fibrinolytic activity and can directly influence platelet function by reducing platelet aggregation. In this study, the effects of reconstituted HDL (rHDL) on LPS-induced coagulation, fibrinolysis and platelet activation in humans were investigated. In a double-blind, randomized, placebo-controlled, cross-over study, eight healthy male volunteers were injected with LPS (4 ng/kg) on two occasions, once in conjunction with rHDL (40 mg/kg, given as a 4 h infusion starting 3.5 h prior to LPS injection), and once in conjunction with placebo. rHDL significantly reduced LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2) and fibrinolysis (plasma levels of tissue type plasminogen activator antigen, t-PA). No effect was observed on LPS-induced inhibition of the fibrinolytic pathway (PAI-1) or on the transient thrombocytopenia elicited by LPS. Furthermore, rHDL treatment significantly enhanced the inhibition of collagen-stimulated inhibition of platelet aggregation during endotoxemia, but had no such effect on arachidonate-stimulated platelet aggregation. rHDL treatment per se also reduced collagen-induced platelet aggregation. These results indicate that rHDL modifies the procoagulant state associated with endotoxemia.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Endotoxemia/tratamiento farmacológico , Fibrinólisis/efectos de los fármacos , Lipopolisacáridos/antagonistas & inhibidores , Lipoproteínas HDL/farmacología , Activación Plaquetaria/efectos de los fármacos , Adulto , Estudios Cruzados , Citocinas/sangre , Método Doble Ciego , Endotoxemia/sangre , Endotoxinas/efectos adversos , Endotoxinas/antagonistas & inhibidores , Humanos , Lipoproteínas HDL/uso terapéutico , Masculino , Fragmentos de Péptidos/análisis , Inhibidor 1 de Activador Plasminogénico/análisis , Agregación Plaquetaria , Protrombina/análisisRESUMEN
High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.
Asunto(s)
Apolipoproteína A-I/metabolismo , Apolipoproteína A-I/uso terapéutico , Colesterol/metabolismo , Colesterol/uso terapéutico , Endotoxemia/tratamiento farmacológico , Endotoxinas/metabolismo , Inflamación/tratamiento farmacológico , Lipopolisacáridos/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/uso terapéutico , Fosfatidilcolinas/metabolismo , Fosfatidilcolinas/uso terapéutico , Adulto , Antígenos CD , Estudios Cruzados , Método Doble Ciego , Granulocitos , Humanos , Infusiones Intravenosas , Interleucina-6/sangre , Interleucina-8/sangre , Recuento de Leucocitos , Masculino , Monocitos , Náusea , Dolor , Placebos , Tiritona , Factores de Tiempo , Factor de Necrosis Tumoral alfa/análisis , VómitosRESUMEN
Reconstituted high-density lipoproteins (rHDL) have been shown bind bacterial LPS and reduce its toxic effects. Since the effect of rHDL on LPS in vitro cannot be directly extrapolated to the in-vivo picture of Gram-negative septic shock, we have investigated the effects of rHDL in a rabbit model of Gram-negative bacteremia. Rabbits were anesthetized, ventilated, and invasively monitored for 6 hours. Escherichia coli (4 x 10(9) CFU/kg) were infused over 2 hours in rabbits given rHDL (75 mg/kg) before the bacterial challenge. Antibiotics were not used in this model. The bacterial infusion resulted in a bacteremia that persisted until the end of the study. The sepsis-induced TNF peak was significantly lowered by rHDL treatment (10 +/- 3 ng/mL in rHDL treated versus 33 +/- 5 in controls, P = 0.001). Blood pressure, although not statistically significant, tended to be higher in the rHDL group. Acidosis was significantly attenuated up to 3 hours after the beginning of the bacterial challenge (7.39 +/- 0.05 versus 7.27 +/- 0.05 in controls, P = 0.041). rHDL treatment produced some transient beneficial effects in this model of persistent Gram-negative bacteremia. Additional studies, investigating the effects of rHDL in combination with antibiotics, are warranted.
Asunto(s)
Bacteriemia/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Lipoproteínas HDL/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Bacteriemia/metabolismo , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/metabolismo , Infecciones por Bacterias Gramnegativas/metabolismo , Lipoproteínas HDL/uso terapéutico , Masculino , Conejos , Proteínas Recombinantes , Choque Séptico/tratamiento farmacológico , Choque Séptico/metabolismoRESUMEN
OBJECTIVES: Reconstituted human high-density lipoprotein (HDL) can inhibit lipopolysaccharide effects in vivo. The major objectives of this study were to characterize the pharmacokinetics of reconstituted HDL in a stressed large-animal model and to provide preclinical tolerance information in support of use of reconstituted HDL in humans. DESIGN: A randomized, blinded, placebo-controlled trial where each animal received either reconstituted human HDL at a dose of 100 mg/kg (apolipoprotein A-I) or placebo, immediately after hemorrhagic shock and resuscitation. SETTING: Animal laboratory. SUBJECTS: Twelve immature female swine (18 to 25 kg) were studied. INTERVENTIONS: Six to 8 days before shock and study drug administration, animals were anesthesized and catheters were placed in the external jugular vein and abdominal aorta. These catheters were secured to the dorsal surface. On the day of shock, the animals were sedated (alpha-chloralose) and 50 mL/kg of arterial blood was removed over 0.5 hr. One half hour after blood removal, shed blood was infused, which was immediately followed by study drug (reconstituted HDL or placebo), and then by 1 L of lactated Ringer's solution. MEASUREMENTS AND MAIN RESULTS: Physiologic (arterial blood pressure, heart rate, respiratory rate) and laboratory (serum chemistries, hematologic and coagulation studies, and blood gases) measurements were determined intermittently for 96 hrs after the induction of shock. Blood was collected intermittently for 48 hrs after shock for assay of apolipoprotein A-I and phosphatidylcholine in plasma. Reconstituted HDL was well tolerated and did not appear to alter the physiologic responses to shock and resuscitation. HDL transient increase in aspartate aminotransferase concentration was noted in the reconstituted group but this increase normalized by 24 hrs after drug administration. Mean apolipoprotein A-I pharmacokinetic parameters were as follows: half-life 24.5+/-5.3 (SD) hrs; clearance 41.9+/-10 mL/hr; and volume of distribution 1.39+/-0.08 L. The apparent mean half-life of phosphatidylcholine was 5.4+/-0.8 hrs. CONCLUSIONS: Reconstituted human HDL was well tolerated in animals that had undergone hemorrhagic shock with resuscitation. The apolipoprotein component of reconstituted HDL had a relatively long half-life, with distribution limited to the vascular space. These findings support the investigational use of this product in humans.
Asunto(s)
Modelos Animales de Enfermedad , Lipoproteínas HDL/farmacocinética , Resucitación , Choque Hemorrágico/sangre , Análisis de Varianza , Animales , Apolipoproteína A-I/sangre , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Lipoproteínas HDL/sangre , Lipoproteínas HDL/uso terapéutico , Distribución Aleatoria , Choque Hemorrágico/terapia , PorcinosRESUMEN
Reconstituted high-density lipoproteins (rHDLs) have the ability to bind bacterial lipopolysaccharide and to reduce its endotoxin activity in vitro and in vivo. The aim of the present studies was to investigate the therapeutic potential of rHDL in bacteremia models. Gram-negative sepsis was induced in anesthetized rabbits by intravenous infusion of Escherichia coli organisms (4 x 10(9) CFU/kg infused over 2 hours) and treated with appropriate antibiotics. rHDL or placebo was infused either before (prophylaxis) or 1 hour after (therapy) the beginning of the bacterial challenge. In the control groups, the bacterial challenge resulted in transient bacteremia, high plasma levels of lipopolysaccharide, secretion of TNF, and symptoms of sepsis, including hypotension and acidosis. rHDL had no influence on blood bacterial counts; however, plasma lipopolysaccharide levels were significantly reduced. Peak plasma TNF concentrations were reduced after prophylactic but not after therapeutic rHDL administration. Both prophylactic and therapeutic rHDL improved clinical outcome: acidosis was significantly attenuated and blood pressure tended to be higher in the rHDL groups. No effects of rHDL were seen in a similar model of gram-positive sepsis induced by the infusion of Staphylococcus aureus.
Asunto(s)
Bacteriemia/tratamiento farmacológico , Infecciones por Escherichia coli/tratamiento farmacológico , Lipoproteínas HDL/farmacología , Sepsis/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Endotoxinas/sangre , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Lipopolisacáridos/sangre , Masculino , Conejos , Infecciones Estafilocócicas/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Reconstituted high-density lipoprotein (rHDL), an artificial lipoprotein consisting of apolipoprotein A-I and phosphatidylcholine (1:150, molar ratios) dose-dependently reduces lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF) production in in vitro, ex-vivo, and in-vivo model systems. In an in-vitro whole blood assay, rHDL (1 mg/ml) added concomitantly with LPS increased cellular resistence to LPS stimulation approximately 1000-fold. Even with extremely high levels of LPS (10 micrograms/ml), rHDL > or = 0.5 mg/ml caused > 50% decrease in TNF production. Preincubation of rHDL with LPS was not required for activity. rHDL (> or = 1 mg/ml) reduced TNF production by 50% even when added to cultures 2 hr after their stimulation with LPS (10 micrograms/ml). In an ex-vivo study, rabbits were infused with rHDL at doses of 25, 50, and 75 mg/kg. Blood was drawn and stimulated with LPS ex vivo and bioactive TNF was assessed using the L929 cytotoxicity assay. Fifteen minutes after rHDL infusion, there was a significant difference in ex-vivo-induced TNF activity between groups (750 +/- 160, 170 +/- 40, 80 +/- 30, 60 +/- 30 pg TNF/ml, for the control, 25, 50, and 75 mg/kg rHDL dose groups, respectively; P < 0.0001). The duration of ex-vivo TNF inhibition was dependent on the dose of rHDL. Even at 2 hr, rHDL showed a pronounced TNF inhibition (control: 950 +/- 120 pg TNF/ml; 75 mg/kg: 140 +/- 60 pg TNF/ml). Further studies showed that a prophylactic infusion of rHDL diminished LPS-induced TNF production in a rabbit endotoxemia model.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Lipopolisacáridos/farmacología , Lipoproteínas HDL/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Endotoxinas/sangre , Masculino , Conejos , Proteínas Recombinantes , Choque Séptico/fisiopatología , Factores de TiempoRESUMEN
Aprotinin reduces blood loss after cardiopulmonary bypass, but may sensitize recipients and is expensive. Tranexamic acid, a synthetic antifibrinolytic, has less disadvantages, but opinions differ regarding its efficacy. We studied three groups of patients undergoing cardiopulmonary bypass for coronary disease: recipients of aprotinin (total dose 4.2 x 10(6) kallikrein inhibiting units, n = 14), recipients of tranexamic acid (total dose 20 mg/kg body weight, n = 15), and nonmedicated controls (n = 14) during 24 hours after cardiopulmonary bypass. Compared with controls, aprotinin reduced blood loss, the number of patients requiring transfusions, and the mean number of transfused red cell units (all with p < 0.05), whereas the recipients of tranexamic acid did not differ either from aprotinin recipients or from controls. Aprotinin and tranexamic acid both mitigated the early postoperative reduction of adenosine diphosphate-induced platelet aggregation seen in the controls (p < 0.05). Postoperative increases of plasma concentrations of the prothrombin activation fragment F1 + 2 and the thrombin-antithrombin III complex showed an activation of intravascular coagulation, without any intergroup differences. The balance between concentrations of tissue plasminogen activator and the type 1 plasminogen activator inhibitor disclosed an activation of fibrinolysis, without differences between the groups. The concentrations of D-dimer, a breakdown product of cross-linked fibrin, remained at baseline in the recipients of aprotinin and tranexamic acid but tripled in the controls (p < 0.05). By contrast, the plasma antiplasmin activity was equally depressed in the tranexamic acid and the control groups but decreased less in the recipients of aprotinin (p < 0.05). This discrepancy may reflect the different modes of action of the two agents, which may make aprotinin more efficacious than tranexamic acid in the "nonfibrinolytic" act of protecting platelet function against attack by plasmin during cardiopulmonary bypass.
Asunto(s)
Aprotinina/administración & dosificación , Pérdida de Sangre Quirúrgica , Puente Cardiopulmonar , Ácido Tranexámico/administración & dosificación , Anciano , Análisis de Varianza , Pruebas de Coagulación Sanguínea , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Puente Cardiopulmonar/estadística & datos numéricos , Enfermedad Coronaria/sangre , Enfermedad Coronaria/cirugía , Transfusión de Eritrocitos , Femenino , Hematócrito , Humanos , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: To determine the effect of reconstituted human high density lipoprotein (rHDL) on physiologic and cytokine responses to infusion of lipopolysaccharide. DESIGN: A blinded, randomized trial of three preparations of a purified human rHDL with apolipoprotein A-I-phosphatidyl choline-cholesterol molar ratios of 1:100:10, 1:150:10, and 1:200:0 and placebo in a rabbit lipopolysaccharide intravenous infusion model. INTERVENTIONS: Groups of six New Zealand white rabbits received either placebo or one of the three human rHDL preparations above as a single, 75-mg/kg (apolipoprotein A-I equivalent) dose intravenously over 10 minutes ending 5 minutes before the start of a 3-hour infusion of lipopolysaccharide. MAIN OUTCOME MEASURES: Mean arterial pressure, base excess, and plasma tumor necrosis factor alpha (TNF-alpha) production were determined. RESULTS: The human rHDL suppressed TNF-alpha production with the products having the highest fraction of phosphatidyl choline producing the greatest suppression of TNF-alpha production. The human rHDL 1:200:0 group maintained a low, near-baseline TNF-alpha concentration and minimal decline in mean arterial pressure and base excess throughout the lipopolysaccharide infusion in contrast to the placebo group. CONCLUSION: Reconstituted human high density lipoprotein appears to be useful in inhibiting the physiologic effects and cytokine release associated with endotoxemia and may provide adjunctive treatment for patients with gram-negative sepsis.
Asunto(s)
Acidosis/fisiopatología , Presión Sanguínea/efectos de los fármacos , Escherichia coli , Lipopolisacáridos/farmacología , Lipoproteínas HDL/farmacología , Factor de Necrosis Tumoral alfa/análisis , Acidosis/sangre , Alcalosis/sangre , Alcalosis/fisiopatología , Animales , Apolipoproteína A-I/administración & dosificación , Apolipoproteína A-I/farmacología , Dióxido de Carbono/sangre , HDL-Colesterol/administración & dosificación , HDL-Colesterol/farmacología , Combinación de Medicamentos , Femenino , Infusiones Intravenosas , Lipoproteínas HDL/administración & dosificación , Oxígeno/sangre , Fosfatidilcolinas/administración & dosificación , Fosfatidilcolinas/farmacología , Placebos , Conejos , Factor de Necrosis Tumoral alfa/efectos de los fármacosRESUMEN
A reconstituted lipoprotein, containing human apolipoprotein A-I and phosphatidylcholine (1:200, molar ratio), referred to as ApoLipo, was used prophylactically in an endotoxin shock model in anesthetized rabbits. ApoLipo was administered at a dose of 75 mg protein/kg body weight 15 min before the beginning of a slow, continuous lipopolysaccharide (LPS, endotoxin) infusion (4.17 micrograms LPS/kg/hr). During the 6 hr LPS infusion, the Control-LPS group manifested a marked increase in serum tumor necrosis factor (TNF, peak value 7.82 [2.7-11.2] ng/ml at 1 hr), and many of the pathophysiologic sequelae of endotoxin shock, including hypotension (MAP: 59 +/- 7 mmHg) and metabolic acidosis (BE: -9.9 +/- 2.7) at 3 hr, and a severe neutropenia developed rapidly (PMN count: 5 +/- 3% of baseline at 30 min). In the ApoLipo treated group, serum TNF levels did not rise during the course of LPS infusion (0.1 [0.06-0.64] ng/ml at 1 hr). Hypotension (77 +/- 2 mmHg) and acidosis (-2.7 +/- 0.4) were also significantly attenuated, and the appearance of leukopenia was delayed by 1 hr (110 +/- 12% at 30 min, but 9 +/- 2% at 2 hr). Endotoxemia in the ApoLipo treated group was reduced in comparison to controls, albeit nonsignificantly. The infusion of the same dose of phosphatidylcholine without apoA-I was significantly less efficacious.
Asunto(s)
Apolipoproteína A-I/farmacología , Choque Séptico/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Acidosis/prevención & control , Animales , Modelos Animales de Enfermedad , Endotoxinas , Hipotensión/prevención & control , Leucopenia/prevención & control , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Fosfatidilcolinas , Recuento de Plaquetas , ConejosAsunto(s)
Endotoxinas/farmacología , Choque Séptico/etiología , Animales , Antígenos Bacterianos/inmunología , Proteínas Sanguíneas/metabolismo , Secuencia de Carbohidratos , Citocinas/metabolismo , Endotoxinas/efectos adversos , Endotoxinas/toxicidad , Humanos , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/metabolismo , Lipopolisacáridos/toxicidad , Lipoproteínas/metabolismo , Ratones , Datos de Secuencia Molecular , Unión Proteica , Ratas , Receptores Inmunológicos/metabolismoRESUMEN
The kinetics of immunoglobulins (Ig) and antibodies were followed in 10 bone marrow transplant recipients who received either high doses (0.5 g/kg body weight) of polyspecific intravenous Ig (HD-IVIG) weekly or cytomegalovirus hyper-Ig (CMV-IVIG, 0.1 g/kg body weight) every 3 weeks. In the HD-IVIG group, the mean total IgG concentration more than tripled and similar significant increases were seen for IgG1 and IgG2. IgG antibodies to CMV showed a marked increase in the HD-IVIG and a less pronounced rise in the CMV-IVIG group. IgM antibodies to CMV were present initially or became detectable in five patients, unrelated to the IVIG preparation. HD-IVIG induced a significant increase of IgG antibodies to streptococcal group A carbohydrate (A-CHO) and to smooth strain lipopolysaccharides (LPS) but not of antibodies against lipid-A. When the Ig treatment was discontinued, levels of total IgG and of IgG antibody to CMV decreased with an apparent half-life of 30 days. Both IVIG preparations were well tolerated and had no negative feedback on total Ig and on specific antibody production or other antimicrobial defence mechanisms. In patient nos. 4 and 10 who developed severe graft-versus-host-disease, transient serum Ig peaks including several Ig isotypes appeared after day 14. In patient no. 10 this peak contained an IgG antibody to H. influenzae type b (Hib), and IgM antibodies to CMV, Hib, A-CHO and LPS. This study clearly shows that serum concentrations of Ig isotypes, subtypes and specific antibodies, depend on at least four factors: total amount and composition of Ig infused, consumption, catabolism and endogenous production.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Isotipos de Inmunoglobulinas/sangre , Inmunoglobulinas/metabolismo , Adulto , Anticuerpos Antivirales/administración & dosificación , Terapia Combinada , Citomegalovirus/inmunología , Femenino , Humanos , Inmunoglobulinas/administración & dosificación , Cinética , Leucemia/inmunología , Leucemia/cirugía , Leucemia/terapia , MasculinoRESUMEN
The use of aprotinin to reduce blood loss after cardiopulmonary bypass is under debate. Concern has been raised about the renal effects of aprotinin. We administered a mean aprotinin dose of 4.2 x 10(6) kallikrein-inhibiting units to 13 patients with coronary disease undergoing cardiopulmonary bypass for 74 +/- 5 minutes (mean +/- standard error of the mean); 13 comparable patients having cardiopulmonary bypass served as control subjects, and all were studied postoperatively for 24 hours. Aprotinin reduced postoperative blood loss by 50% (p = 0.0082). Two of the 13 patients who received aprotinin needed one red cell unit each versus a total of 18 units in eight of 13 control patients (p = 0.0096). Blood pressure, hemoglobin value and serum protein concentration were higher after operation in the aprotinin group (p less than 0.05 to p less than 0.01). Platelet counts did not differ, but plasma thromboxane was lower in aprotinin recipients (p less than 0.001). In control patients fibrinogen degradation products (D dimer) doubled, and alpha 2-antiplasmin activity was halved during and after cardiopulmonary bypass (p less than 0.01 to p less than 0.001), whereas aprotinin patients showed no changes. The complement breakdown products C4a, C3a, and C3dg as well as C9 neoantigen increased from prebypass baseline in both groups (p less than 0.001); the increment of C3a and C3dg was greater in the aprotinin than in the control patients (p less than 0.001). Serum electrolytes, osmolality, and creatinine remained normal in both groups of patients. Creatinine clearance was normal or above normal and virtually identical in both groups. Osmolar clearance and fractional sodium excretion were higher in the aprotinin group than in the control group shortly after cardiopulmonary bypass (p less than 0.05 to p less than 0.01); renal function was unremarkable the next morning. No adverse clinical effects attributable to aprotinin were seen. In summary, aprotinin offers advantages for cardiopulmonary bypass.
Asunto(s)
Aprotinina/administración & dosificación , Pérdida de Sangre Quirúrgica , Plaquetas/efectos de los fármacos , Puente Cardiopulmonar , Proteínas del Sistema Complemento/efectos de los fármacos , Fibrinólisis/efectos de los fármacos , Riñón/efectos de los fármacos , Antitrombina III/análisis , Antitrombina III/efectos de los fármacos , Aprotinina/uso terapéutico , Plaquetas/fisiología , Presión Sanguínea/efectos de los fármacos , Transfusión Sanguínea , Proteínas del Sistema Complemento/análisis , Creatina/sangre , Electrólitos/sangre , Factor VIII/análisis , Factor VIII/efectos de los fármacos , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Tasa de Filtración Glomerular , Hemoglobinas/análisis , Hemostasis Quirúrgica , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Tromboxano A2/sangre , Urea/sangreRESUMEN
It has long been hypothesized that fibronectin (Fn) is essential to the function of the reticuloendothelial system (RES) and that the reversal of Fn deficiency in critically ill patients would result in a clinical benefit to these patients. Fn administration to deficient patients was postulated to improve the function of the RES, decrease the incidence of organ failure, sepsis and ultimately mortality. Over the past 15 years, several clinical studies have been performed to test these hypotheses. The initial anecdotal studies using cryoprecipitate (a plasma fraction enriched in Fn) revealed promising results but were neither controlled nor blinded. Further controlled studies were published utilizing both cryoprecipitate and purified Fn. Unfortunately, the great majority of authors found no beneficial effects of Fn administration in critically ill patients, in relation to incidence of organ failure, sepsis, or mortality. These results do not support the use of Fn in this setting. Fn utilization in wound healing has shown promising results in case reports. Although its role in wound healing is not yet fully delineated, initial reports with corneal wounds show a beneficial influence of Fn administration. Further studies are needed to determine the exact function(s) of Fn in a healing wound. Efficacy must still be shown in controlled clinical trials; dosing and administration regimens need to be elucidated.
Asunto(s)
Fibronectinas/uso terapéutico , Sistema Mononuclear Fagocítico/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Ensayos Clínicos como Asunto , Factor VIII/uso terapéutico , Fibrinógeno/uso terapéutico , Humanos , Sistema Mononuclear Fagocítico/fisiología , Cicatrización de Heridas/fisiologíaRESUMEN
We determined isotypes of natural antibodies to streptococcal group A carbohydrate (A-CHO) in sera from 101 children between 1 and 16 years of age, using a calibrated enzyme-linked immunosorbent assay system. Anti-A-CHO IgM could be detected in all but one sera. Median levels increased with age and were highest between 8 and 12 years. IgG antibodies were present at low concentrations up to the age of 4 years, and consisted predominantly of the IgG1 subclass. Between 4 and 8 years, concentrations of anti-A-CHO IgG markedly increased and median levels continued to increase through age 12-16. Anti-A-CHO IgG1 levels closely followed the pattern of IgG antibody concentrations. The number of IgG2 antibody positive sera was low in young children, as expected. In the 8-12 year age group and later, anti-A-CHO IgG2 was present in more than half of the samples, and in children between 12 and 16, medians of IgG2 and IgG1 antibodies were similar. Sera containing anti-A-CHO IgG3 were rare in children up to 4 years of age, but in the group of 4-8-year-old children, this subclass was detectable in 36% and later in up to 77% of the sera. Thus, the IgG response to A-CHO showed a clear maturation during childhood, involving the subclasses IgG1, IgG2 and IgG3. There were no significant differences in A-CHO levels between boys and girls.
Asunto(s)
Envejecimiento/inmunología , Anticuerpos Antibacterianos/biosíntesis , Polisacáridos Bacterianos/inmunología , Streptococcus pyogenes/inmunología , Adolescente , Anticuerpos Antibacterianos/inmunología , Niño , Preescolar , Humanos , Inmunoglobulina G/análisis , Isotipos de Inmunoglobulinas/análisis , Inmunoglobulina M/análisis , LactanteRESUMEN
At rest, the actual cardiac output (CO) exceeds the CO required to cover the oxygen consumption VO2, provided the hemoglobin level and the non-Hb parameters impacting on cellular oxygen supply (e.g. paO2, pH and body temperature) are normal. The size of this hemodynamic buffer as a function of Hb levels and the non-Hb parameters can be quantified for any clinically conceivable combination including VO2. As Hb levels decrease, the patient's condition is progressively destabilized in the sense that the gradual vanishing of the buffer makes him increasingly sensitive to abnormalities of the non-Hb parameters, such as hypermetabolism, arterial hypoxemia, and alkalosis. This concept is used to illustrate the course of patients participating in an autologous blood predeposit program.
Asunto(s)
Transfusión de Sangre Autóloga/instrumentación , Hemoglobinometría/instrumentación , Microcomputadores , Anestesia General , Humanos , Concentración de Iones de Hidrógeno , Oxígeno/sangre , Fumar/sangre , Programas InformáticosRESUMEN
Eighty-five trauma patients between the ages of 18 and 55, with American College of Surgeon's (ACOS) trauma scores greater than or equal to 7 were entered into a double-blind, randomized, placebo-controlled study to assess the efficacy of prophylactic fibronectin (Fn) administration on clinical course, sepsis development, and septic mortality. Patients were randomized on admission to receive purified human virus-inactivated Fn or placebo control (human serum albumin, HSA). Fn or HSA was administered on a daily basis if and when the patient was Fn deficient (less than 75% normal). When a Fn deficiency was not evident, the patient received saline. Seventy one patients developed Fn deficiencies during their initial clinical course: 36 received Fn, 35 received HSA. Fourteen patients did not develop a Fn deficiency after trauma and thus received only saline. Analysis of admission data demonstrated no significant differences between the three groups with respect to extent of injury (injury severity score, ACOS trauma score) or physiologic assessments of organ function (serum creatinine, bilirubin, lactic acid). On day 1 after trauma, Fn levels were shown to correlate with other plasma proteins and cellular components (range of r values, 0.24 to 0.75; all p less than 0.05), but not with organ function parameters. Eighteen of 85 patients became septic as judged by clinical criteria. Ten of these patients had received Fn (10 of 36), five had received HSA (5 of 35), and three had received only saline (3 of 14) before the development of sepsis (differences not significant). When septic, nine of 17 patients developed Fn deficiencies. Six patients received Fn while septic, three received albumin, and eight received saline. Seven patients died: 5 of 6 Fn patients, 1 saline, and 1 HSA recipient. Our data suggest that exogenous Fn repletion in states of deficiency does not alter clinical course, the development of sepsis, or septic mortality.